Aerosol dilating medical composition



Patented June 22, 1954 AEROSOL DILATING MEDICAL CDMPOSITION Lucien Dautrebande, Brussels, Belgium, assignor to Aerosol Corporation of America, New York, N. Y., a corporation of Delaware No Drawing. Application octobei- 25, 1951, Serial No. 253,225

Claims. 1

This invention relates to aerosol medication and more particularly to therapeutic solutions suitable for inhalation as aerosols in the treatment of asthma and related disorders.

For the successful treatment of bronchial asthma, status asthmaticus and other diseases characterized by spastic bronchoconstriction, it is necessary to employ drugs which exercise a pneumodilating action. In the use of such drugs, a problem has existed with respect to bringing the therapeutic agents into contact with the constricted bronchial mucosa in order to produce pneumodilatation. It has been found that the administration of sympathomimetic drugs by means of aerosols, i. e., dispersions in air of solutions of the drugs, in which the individual particles present are of the order of one micron or less in size, makes possible the penetration of the lungs by these therapeutic agents so that their beneficial therapeutic effects may be exerted directly upon the bronchial mucosa. Thus, it has been possible to bring about effective pneumodilatation by means of sympathomimetic drugs without employing parenteral administration.

Heretoiore 1(3',4 dihydroxyphenyl) -2-isopropylaminoethanol, commonly known as 'Alu- 'drine, has been found to be an exceedingly efiicient drug for the treatment of asthma, and solutions of Aludrine have been administered therapeutically as aerosols by inhalation for purposes of treatment of asthmatic conditions and the like. It has been found, however, that where solutions of Aludrine are employed in sufficient concentration to bring about a full pneumodilaml pneumodilating effect without danger of side effects or toxic manifestations through long-corn.

tinued therapeutic use. It is a further object of this invention to provide therapeutic solutions which when inhaled in the form of an aerosol are capable of exerting a maximum pneumodilating efiect. A further object of this invention is the provision of therapeutic solutions for use as aerosols in which the ingredients are individually present in quantities proportionately much smaller than has heretofore been and one or more bronchodilating agents selected from the group consisting of 1-(3',4-dihydroxyphenyl) 2 isopropylaminoethanol (Alutation, as is generally desirable, it is practically impossible to avoid the occurrence or" unpleasant side effects. Other substances, such as epinephrine, ephedrine, atropine, amphetamine, and the like, although somewhat less effective, have also been used in the treatment of asthma. However, because of the appearance of side effects or actual toxic manifestations during or after the period of treatment, the therapeutic application of sympathomimetic drugs in diseases characterized by the occurrence of spastic bronchoconstriction has had to be carefully regulated. It has generally been necessary to provide rigid schedules of administration for the aforementioned drugs to prevent their too frequent use, in order to'minimize the occurrence of the undesirable and even dangerous side eifects.

It is an object of this invention to provide a solution for therapeutic administration by inhalation as an aerosol, which exercises a Power-- drine), and cyclopentylmethylaminopropane (cyclopentamine), and/or salts of said agents have especially valuable properties for inhalation treatment of asthma and other diseases in which pneumodilatation is of therapeutic benefit. The new compositions of my invention contain procaine and pneumodilating drugs in smaller amounts than would be expected for full therapeutic effect, because of synergistic action between the procaine and the sympathomimetic ingredients whereby their pneumodilating action is markedly potentiated. When administered as aerosols, the new compositions afford dramatic relief in cases of asthmatic crisis. Moreover, no appreciable side effects and no toxic symptoms are evidenced even though ad ministration of the solutions as aerosols is relatively long-continued or often repeated.

The vehicle or diluent employed in the new compositions can be any of the pharmaceutical diluents already known to the art not to be harmful to the lung tissues when inhaled as an aerosol. Examples of suitable diluents include Water, isotonic salt solution, the lower glycols such as triethylene glycol and propylene glycol, especially aqueous solutions of these glycols, and the like.

Procaine and the other bronchodilating agents contained in the novel compositions are organic bases and are generally used in the form of their pharmaoeutically useful water soluble acid addition salts where the composition contains an aqueous vehicle. By the term pharmaceutically useful it is intended to designate those salts which donot substantially increase the toxicity of the base, and which are compatible with the vehicle employed. Examples of such salts are the hydrochloride, sulfate, nitrate, phosphate, hydrobromide, acetate and like salts of the procaine and the sympathomimetic bases. However,

Cyclopentylmethylaminopropane h y d r ochloride 0.5

Propylene glycol 80 Water to make 100 g.

. 5 The solution is placed in an aerosolizer and It s p gi z f i m the s several inhalations are made of the aerosol 1c g f 01 ases g 2 E which is produced. The treatment can be ree yco car} 8 use an peated at hourly intervals, or more frequently as with such vehicles the active substances can renuired to rovide relief loyed in the form of their bases p be emp 1 h n 10 Other materials can, if desired, be included in Procame1lsgmp oyead m t e i a the compositions of this invention in order to m concentlgtlollll of fi l Jo g obtain special therapeutic or other effects not percent t e f P ommetlc g g achieved by the presence of only the combination z g conceglbm mm t of the procaine and sympathomimetic amine. g f i y g f g Thus, for example, anti-secretive drugs such as 2 ml gercennof 5100a 3 atropine, antiseptics for the respiratory system t. peluin 3 j omme 10 such as creosote, guaiacol, menthol, eucalyptol 12g W 10 is e1fnp 0y? ailetpresen 1 1 f 1 q and the like, isotonicity-producing substances n g' e s mben 3 1 such as sodium chloride and the like, additional g g g f an m f f 1 20 vehicles such as propylene glycol, triethylene j e nove 6 e0 5 of my as glycol and the like, chemotherapeutic agents 0 EXAMPLE 1 such as the sulfonamides, and antibiotics including penicillin, streptomycin, Aureomycin, Chloro- Procaine hydrochloride g 1 mycetin, bacitracine, tyrotricine, and the like can 1(3,4' dihydroxyphenyl)2-isopropylarninobe employed if desired in conjunction with the ethanol hydrochloride g 0.5 fundamental ingredients of the compositions of Water to make 100 cc. the invention as shown in Example 1. The fol- Acid addition salts of cyclopentylmethylaminolowing examples illustrate compositions providpropane can be used together with or in place ing effective pneumodilatation, thus permitting a of the Aludrine. better penetration of the lung tissues by the For therapeutic use, the above solution is placed g p i i i 3 p f drug. y fi in any of the commercially available devices ,lermn P if Ions ale (.ispema use u known as aerosolizers or nebuhzers and from in bacterial infections of the respiratory t1 act. two to ten or more inhalations are madeof the r EXAMPLE 3 aerosol which is produced therefrom. A lasting 1 pneumodilatation takes place, with relief from P10931119 Pydlocnloude asthmatic symptoms. The treatment is repeated 1(3 dlhydroxyphenyl) as indicated, propylaminoethanol sulfate"- 0.25 g.

The synergistic eiiect obtainable in this com- 0 Sodium Penicillin-G 1 million units. position is demonstrated by the following: 4 Water to make 100 cc.

Table Volume Dilation Range Duration oi Aero- (Maximum Inof Dila- Example No. Aerosol ofsol increaseinactuai tion (in haled (in Lung Volume minliters) in cc.) utes) A 1% aqueous solution of pro- 12 150 to 250 2 to 3.

caine hydrochloride. B 05% aqueous solution of 12 300 to 500 4t0 G.

l (3',4 dihydroxyphenyl) 2 isopropylaminoethanol hydrochloride. 1 Aqueous solution contain- 12 1,000 to 1,200 10 to 15.

ing 1% procaine hydrochloride and 0.5% of 1(3,4 dihydroxyphenyl) 2 isopropylaminoethanol hydrochloride.

EXAMPLE 2 Procaine hydrochloride 0.2 1(3,4' dihydroxyphenyl) -2-isopropylaminoethanol hydrochloride 0.25 Atropine sulfate 0.1

Ten to twenty inhalations of a fine aerosol or more of the above composition produces a substantial pneumodilatation and concomitantly provides a more uniform and penetrating pulmonary penicillin therapy.

EXAMPLE 4 Procaine hydrochloride 0.2 Cyclopentylmethylaminopropane hydrochloride 0.5 l (3,4' -dihydroxyphenyl) -2-isopropylaminoethanol hydrochloride 0.25 Streptomycin hydrochloride 5.0

Water to make cc.

The solution is placed in an aerosolizer and from ten to twenty inhalations or more are made at each treatment. The entry of the streptomycin into the lung passages is facilitated by the pneumodilatation which takes place.

I claim:

1. A composition adapted for inhalation as a therapeutic aerosol, comprising a solution of procaine hydrochloride, 1(3,4'-dihydroxyphenyl)-2-isopropy1aminoethanol hydrochloride, and cyclopentylmethylaminopropane hydrochloride in a vehicle which is without harmful effect on lung tissue.

2. A composition adapted to inhalation as a therapeutic aerosol, comprising about 0.2 percent procaine hydrochloride, about 0.25 percent 1(3',4-dihydroxyphenyl) Z-isopropylaminoethanol hydrochloride, and about 0.5 percent cyclopentylmethylaminopropane hydrochloride dissolved in a pharmaceutical 'diluent.

3. A composition adapted for inhalation as a therapeutic aerosol, comprising a solution in a pharmaceutical diluent of a member of the group consisting of procaine and pharmaceutically useful acid addition salts thereof, together with at least one member of the group consisting of 1(3',4=-dihydroxyphenyl)- 2 isopropylaminoethanol and cyclopentylmethylaminopropane, and pharmaceutically useful acid addition salts thereof.

4. A pneumodilating aerosol composition comprising a solution in a pharmaceutical diluent of from about 0.1 to 1.5 percent of a member of the group consisting of procaine and pharmaceutically useful acid addition salts thereof, and from about 0.1 to 1.0 percent of a member of the group consisting of 1(3,4-dihydroxyphenyl) -2- isopropylaminoethanol, and cyclopentylmethylaminopropane and pharmaceutically useful acid addition salts thereof.

5. A pneumodilating aerosol composition comprising from about 0.2 to about 0.5 percent of a member of the group consisting of procaine and pharmaceutically useful acid addition salts thereof, and from about 0.2 to about 0.5 percent of at least one member of the group consisting of 1(3',4'-dihydroxyphenyl) -2-isopropylaminoethanol and cyclopentylmethylaminopropane, and pharmaceutically useful acid addition salts thereof.

6. A pneumodilating aerosol composition comprising a pharmaceutical diluent and dissolvent therein in a total concentration less than about 2.5 percent, a mixture of procaine hydrochloride and 1 (3',4=-dihydroxyphenyl) -2-isopropy1aminoethanol hydrochloride.

7. A pneumodilating aerosol composition comprising a solution in a pharmaceutical diluent of about 0.2 percent of procaine hydrochloride and about 0.25 percent of 1(3',4-dihydroxyphenyl) -2-isopropylaminoethanol hydrochloride.

8. A composition adapted for inhalation as a therapeutic aerosol, comprising a solution of procaine hydrochloride, 1 (3',4'-dihydroxyphenyl) -2- isopropylaminoethanol hydrochloride, cyclopentylmethylaminopropane hydrochloride in a vehicle which is without harmful effect on 11mg tissue and an antibiotic.

9. A composition adapted for inhalation as a therapeutic aerosol, comprising a solution of procaine hydrochloride, 1(3,4'-dihydroxyphenyl)- 2-isopropylaminoethanol hydrochloride, cyclopentylmethylaminopropane hydrochloride in a vehicle which is without harmful effect on lung tissue and penicillin.

10. A composition adapted for inhalation as a therapeutic aerosol, comprising a solution of procaine hydrochloride, 1(3',4-dihydroxyphenyl)-2-isopropylaminoethanol hydrochloride, cyclopentylmethylaminopropane hydrochloride in a vehicle which is without harmful effect on lung tissue and streptomycin.

References Cited in the file of this patent UNITED STATES PATENTS Number Name Date 2,350,318 Shonle May 30, 1944 2,520,015 Rohrman Aug. 22, 1950 OTHER REFERENCES Physicians Bulletin, November to December 1950, pages 163 to 170.

Cobe: J. A. Pharm. A., February 1949, pages 88 to 90.

Dautrebande: Arch. Int. Pharmacodyn, vol. 66, pages 379 to 396 (pages 383, 392 especially relied upon).

Dautrebande: Arch. Int. Pharmacodyn., vol. 68, pages 117 to 210 (pages 117, 122, 130, 139, 199 to 206 especially relied upon). 

1. A COMPOSITION ADAPTED FOR INHALATION AS A THERAPEUTIC AEROSOL, COMPRISING A SOLUTION OF PROCAINE HYDROCHLORIDE, 1(3'',4'' -DIHYDROXYPHENYL) -2-ISOPROPYLAMINOETHANOL HYDROCHLORIDE, AND CYCLOPENTYLMETHYLAMINOPROPANE HYDROCHLORIDE IN A VEHICLE WHICH IS WITHOUT HARMFUL EFFECT ON LUNG TISSUE. 